RESUMO
In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1-/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.
Assuntos
Síndrome do Cromossomo X Frágil , Camundongos , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Proteostase , Bortezomib/metabolismo , Bortezomib/uso terapêutico , Proteína do X Frágil da Deficiência Intelectual/genética , Modelos Animais de Doenças , Camundongos KnockoutRESUMO
Las practicas de conservacion y restauracion del patrimonio historico cultural de nuestro pais son relativamente recientes.En la nota se presentan los resultados y las conclusiones de investigaciones llevadas a cabo sobre esculturas en metal y piedra expuestas a la intemperie natural en ambientes urbanos,las que sufren el daño provocado por la accion de agentes meteoricos y por la presencia de contaminantes ambientales tipicos de las grandes ciudades
Assuntos
Poluentes AmbientaisRESUMO
Las practicas de conservacion y restauracion del patrimonio historico cultural de nuestro pais son relativamente recientes.En la nota se presentan los resultados y las conclusiones de investigaciones llevadas a cabo sobre esculturas en metal y piedra expuestas a la intemperie natural en ambientes urbanos,las que sufren el daño provocado por la accion de agentes meteoricos y por la presencia de contaminantes ambientales tipicos de las grandes ciudades
